This program-project consists of studies aimed at the elucidation of certain aspects of mental retardation. Investigations will be concerned with the mechanisms of biosynthesis and control of biosynthesis of proteoglycans. Studies of the mechanism of differentiation will continue, using a tissue culture system which permits the change of chick limb bud mesenchyme to cartilage. It is hoped to study the changes in the cell during differentiation which lead to the synthesis of large amounts of cartilage-specific products, namely type II collagen, chondroitin sulfate proteolgycan, and link proteins. The genes for these proteins are being cloned in order to develop probes for measurement of changes in the genome or expression of appropriate mRNA. Clonal antibodies have been developed for the specific identification of core protein of chondroitin sulfate proteoglycans. A number of human heritable diseases involve defects in degradation of glycosaminoglycans, glycosphingolipids, and glycoproteins. Studies are continuing to elucidate the enzyme defects of these diseases as well as certain animal models. It is hoped that these may serve as bases for improved methods of diagnosis and perhaps point to future methods of treatment. Cultured cells of neural origin are being used to study the mechanism of synthesis of glycoproteins and glycolipids and the possible effects thereon of opiates, enkephalins and related compounds. The fine structure of the human cortex in normal and mentally retarded individuals is being investigated as well as dendritic development in a tissue culture system.